Targeted radionuclide therapy (TRT) and radioimmunotherapy (RIT) are at the forefront of molecular cancer treatment modalities that involve the use of cancer cell-targeting radiopharmaceuticals, such as radiolabeled antibodies, which selectively concentrate in tumor cells. These Y-90 based therapies have thus far been hampered by the inability to accurately image and quantify the distribution of Y-90 within the body as the latter is a pure 2 emitter. Quantitative Y-86 PET imaging would allow personalized patient treatment by enabling tailored Y-90 TRT based on the quantitative biodistribution of Y-86 uptake. However, Y-86 PET presents unique challenges as it requires compensation for many physical effects including gamma cascade, scatter and random coincidences that greatly affect image quality and accuracy. The aims of this proposal are to accurately model PET imaging using isotopes with cascade gammas, develop correction algorithms to achieve quantitative PET, and evaluate the impact of improved Y-86 quantitation on Y-90 dosimetry. Specific corrections for gamma cascade coincidence and Compton scatter as well as customized iterative tomographic reconstruction will be developed for isotopes emitting prompt single gammas in the challenging case of Y-86 imaging and can be generalized to other isotopes. Our methods will be validated in realistic Monte Carlo simulations and corresponding phantom experiments. PUBLIC HEALTH RELEVANCE: Y-90 is a promising isotope for Targeted radionuclide therapy (TRT) and radioimmunotherapy (RIT). Quantitative Y-86 PET allows to tailor the patient treatment but requires compensation for gamma cascade, scatter and prompt coincidences. The aim of this proposal is to achieve quantitative PET using isotopes with cascade gammas for personalized radionuclide therapy.